title: Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors.
abstract: BACKGROUND
  Previous studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure.
  
  
  METHODS
  Cell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed.
  
  
  RESULTS
  vvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors.
  
  
  CONCLUSIONS
  Oncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.
authors.affiliation: Pediatric Oncology Experimental Therapeutics Investigators Consortium (POETIC) Laboratory for Pre-Clinical and Drug Discovery Studies, University of Calgary, Canada and Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta, Canada.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Lun
authors.forename: Yibing
authors.initials: Y
authors.lastname: Ruan
authors.forename: Aarthi
authors.initials: A
authors.lastname: Jayanthan
authors.forename: David J
authors.initials: DJ
authors.lastname: Liu
authors.forename: Anjali
authors.initials: A
authors.lastname: Singh
authors.forename: Tanya
authors.initials: T
authors.lastname: Trippett
authors.forename: John
authors.initials: J
authors.lastname: Bell
authors.forename: Peter
authors.initials: P
authors.lastname: Forsyth
authors.forename: Randal N
authors.initials: RN
authors.lastname: Johnston
authors.forename: Aru
authors.initials: A
authors.lastname: Narendran
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D007223:Infant; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D009447:Neuroblastoma / Q000235:genetics / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D012509:Sarcoma / Q000150:complications / Q000235:genetics / Q000628:therapy; D014616:Vaccinia virus / Q000235:genetics / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
keywords: Atypical teratoid rhabdoid tumors (AT/RT); Double-deleted vaccinia virus; Neuroblastoma; Oncolytic virus; Pediatric tumors; Sarcoma